DESCRIPTION: (Applicant's Abstract) Drug use by the inhalation route continues to rise as an increasing number of individuals discover that inhalation is a highly efficient, cost effective means of drug delivery that obviates the possible transmission of communicable diseases associated with i.v. administration. Our goal is to develop animal models of drug inhalation in order to identify drug toxicities that are unique to this route of administration. Several classes of abused drugs will be examined because they represent distinctly different problems that arise from inhalation. Cocaine will be examined because it was found to produce cardiotoxicity in rats allowed to inhale cocaine vapor but not following i.v. administration. Our goal is to identify the mechanism by which cocaine produces bradyarrthymias and determine whether tolerance or sensitization develops to this cardiotoxicity following repetitive cocaine exposures. Experiments will also be carried out to determine whether cocaine metabolites and drugs that are frequently co-abused with cocaine exert any influence on cocaine cardiovascular effects. The popularity of drug inhalation has increased dramatically for both heroin and methamphetamine. While the effects of acute inhalation of methamphetamine, heroin and phencyclidine are similar to an i.v. administration, the consequences of chronic inhalation is unknown, especially with regard to the development of tolerance and dependence. Although most drugs are inhaled in vaporized form, marijuana represents the major illicit drug that is primarily smoked. Despite extensive research on delta-9 THC, the major psychoactive constituent in marijuana, there are numerous unanswered questions regarding marijuana itself. The development of cannabinoid behavioral models, inhalation procedures for exposing mice and rats to marijuana smoke, a specific cannabinoid antagonist and a delta-9 THC dependence model allow us to address some of the questions that were heretofore not possible. The objectives of the grant are to address questions as to whether other constituents in marijuana contribute to delta-9 THC s effects and whether all marijuana effects can be blocked by the specific cannabinoid antagonist. Studies will be carried out to determine whether other drugs, such as ethanol, potentiate the effects of marijuana. It will be important to determine whether mice and rats repetitively exposed to marijuana smoke develop tolerance and dependence comparable to that produced by delta-9 THC. Finally, efforts will be made to develop a volatilized form of delta-9 THC which would be preferable to oral administration of dronabinol for therapeutic uses.